Collapse of Intra-Tumor Cooperation Induced by Engineered Defector Cells

Our plain-English summary of Collapse of Intra-Tumor Cooperation Induced by Engineered Defector Cells, by M. Archetti (Cancers, 2021).

The study

• Author: M. Archetti
• Journal: Cancers
• Published: 2021;13(15)
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Anti-cancer therapies promote clonal selection of resistant cells that evade treatment. Effective therapy must be stable against the evolution of resistance. A potential strategy based on concepts from evolutionary game theory is to impair intra-tumor cooperation using genetically modified cells in which genes coding for essential growth factors have been knocked out. Such engineered cells would spread by clonal selection, driving the collapse of intra-tumor cooperation and a consequent reduction in tumor growth. Here, I test this idea in vitro in four cancer types (neuroendocrine pancreatic cancer, mesothelioma, lung adenocarcinoma and multiple myeloma). A reduction, or even complete eradication, of the producer clone and the consequent reduction in cell proliferation, is achieved in some but not all cases by introducing a small fraction of non-producer cells in the population. I show that the collapse of intra-tumor cooperation depends on the cost/benefit ratio of growth factor production. When stable cooperation among producer and non-producer cells occurs, its collapse can be induced by increasing the number of growth factors available to the cells. Considerations on nonlinear dynamics in the framework of evolutionary game theory explain this as the result of perturbation of the equilibrium of a system that resembles a public goods game, in which the production of growth factors is a cooperative phenotype. Inducing collapse of intra-tumor cooperation by engineering cancer cells will require the identification of growth factors that are essential for the tumor and that have a high cost of production for the cell.

In plain English

This laboratory study combined in vitro cell-culture experiments with a mathematical model from evolutionary game theory to test whether cancer cells engineered to stop producing a growth factor can spread among producing cells and slow growth. Four cell lines each had one growth-factor gene knocked out: IGF2 in murine βTC neuroendocrine pancreatic cancer cells, IL6 in U266B1 multiple myeloma and A549 lung cancer cells, and PDGFD in NCIH28 mesothelioma cells. Starting from 1% knockout cells in 200,000 wild-type cells and passaging 12 times at 2%, 5% or 10% fetal bovine serum, the knockout clone replaced the wild-type clone in βTC (at 10% serum) and U266B1 (at 5% and 10%) and coexisted with it in A549. In NCIH28 it never invaded at low serum but rose from 1% to 9% at 10% serum, a possible slow increase. Estimated cost/benefit ratios were 0.28 (βTC), 0.33 (U266B1), 0.04 (A549) and 0.02 (NCIH28). The author concluded the main postulate seemed validated in some cases and the approach feasible in principle, with identification of suitable growth factors, delivery and efficacy still to be tested.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: In vitro cell-line experiments (long-term mixed-culture passaging and growth-rate assays) combined with a mathematical model of evolutionary game theory; presented by the author as a proof of principle
• Who was studied: Four cancer cell lines: U266B1 (multiple myeloma), A549 (non-small cell lung cancer), NCIH28 (mesothelioma) from ATCC, and murine βTC (neuroendocrine pancreatic cancer); each with a wild-type and a knockout clone
• Exposure: Genetic knockout of a growth-factor gene (IGF2, IL6 or PDGFD) in each cell line, mixing 1% knockout cells into wild-type populations, with growth medium containing 2%, 5% or 10% fetal bovine serum and, in some experiments, added recombinant growth factor
• Main results:
  • In βTC cells, the IGF2 knockout clone took over the population at 10% FBS, reached an apparently stable mixed equilibrium at 5% FBS, and did not invade at 2% FBS
  • The U266B1 IL6 knockout clone always invaded, replacing wild-type cells at 5% and 10% FBS and reaching a mixed equilibrium at 2% FBS
  • The A549 IL6 knockout clone invaded but only reached a stable mixed equilibrium at all FBS levels
  • In the mesothelioma line NCIH28, the PDGFD knockout clone did not invade at low FBS, but at 10% FBS rose from 1% to 9%, which the author described as perhaps a sign of a slow increase
  • Growth of the final mixed βTC populations was slower than the initial populations: 72% slower at 10% FBS, 65% slower at 5% FBS, 25% slower (not significant) at 2% FBS
  • In NCIH28 mesothelioma cells, growth rates of initial and final populations did not differ significantly at any FBS level
  • Without added growth factor, pure knockout populations grew significantly less than wild-type: βTC 79% less, U266B1 55% less, A549 39% less, NCIH28 79% less
  • Estimated cost/benefit ratios of growth factor production were high in U266B1 and βTC and low in A549 and NCIH28
  • In βTC populations at mixed equilibrium, raising FBS to 10% for six passages made the shift irreversible: the knockout clone kept increasing after FBS was reduced back to 5% and drove the wild-type clone to extinction
• The authors' conclusion: The author concluded that the main postulate, that a small fraction of knockout non-producer cells can drive producer cells to extinction, seemed validated in some cases, and that the feasibility of the approach seemed validated in principle, while identifying appropriate cell types and growth factors and testing engineering, delivery and efficacy remained
• Limitations the authors state:
  • The model assumes a well-mixed population, which does not fit the cell lines grown in monolayers, and a spatially structured model would be more realistic
  • Key parameters of the benefit function (steepness, inflection point, group size) were not known or measured
  • In vitro results may not hold in vivo and should be repeated in an animal model
  • The βTC knockout cells were not autologous to the βTC wild-type cells, so lack of IGF2 may not be their only difference
  • The long deletion in the NCIH28-ΔPDGFD clone may have had deleterious effects, a potential confounding issue
  • Identifying the growth factors and cancer types or patients meeting the required conditions was not addressed in this study

Topics

Medical terms in this study, explained in our Lexicon: Clonal Selection, Mesothelioma, Lung Adenocarcinoma, Myeloma.

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